Health status based on EQ-5D-5L for the cancer patient population in Malaysia

The EQ-5D is a common generic tool used in clinical trials and economic evaluations to evaluate the health-related quality of life as a proxy of health outcomes. To date, studies using EQ-5D-5L to evaluate the health status of cancer patients remain scarce in Malaysia. In this study, EQ-5D-5L dimensions, EQ-5D-5L index, and EQ-VAS scores were applied to assess the health status of Malaysian cancer patients. A cross-sectional study was conducted March-December 2022 to collect data relevant to the EQ-5D-5L valuation of health status via the Research Electronic Data Capture (REDCap) platform. Respondents rated their health states using EQ-5D-5L and EQ-VAS. Among the 235 respondents, the mean EQ-5D-5L index and EQ-VAS score were 0.76 (SD 0.223) and 81.06 (SD 16.36). Most of the patients reported some problems in the pain/discomfort and anxiety/depression dimensions. The level of education, stage of cancer, and comorbidity were significantly associated with better health status on EQ-5D-5L (p < 0.05) but only the stage of cancer was significantly associated with EQ-VAS scores. This study highlighted the disparities in self-reported health status across patients of different sociodemographic and medical profiles with EQ-5D-5L valuation. Thus, future research should use EQ-5D norm scores as a benchmark of comparison among cancer patients.

Globally, cancer contributes to a high level of morbidity and mortality 1 .Over the last few decades, many steps have been taken to lower the disease burden of cancer.However, the incidence of cancer continues to increase 2 .In Malaysia, as high as 115,238 new cancer cases were reported between 2012 and 2016 3 .It also ranks as the second commonest cause of death.In 2016, breast cancer had the highest incidence rate in Malaysia at 17.3% followed by colorectal cancer at 13.6% and lung cancer at 8.7% 4 .These three types of cancer, make up half of all reported cancer cases in Malaysia.Unfortunately, these cancers are often diagnosed at an advanced stage.
The escalating cancer incidence has caused a great concern in the country, especially with the implications on the healthcare system and the quality of life (QoL) of affected patients as they require more medical attention 5 .The growing need for health economic evaluation arises due to scarcity of resources and escalating expenses associated with medical care especially for cancer diseases 6 .Cost utility analysis (CUA) is a favoured approach in health economic evaluation, wherein the measurement of health outcomes is conducted by utilizing qualityadjusted life years (QALYs) 7 .Measuring the health status of cancer patient is essential for effective treatment,

EQ-5D-5L dimensions
In the EQ-5D-5L, respondents will score the five dimensions of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) on five levels of severity, ranging from 1 = "no problems", 2 = "slight problems", 3 = "moderate problems", 4 = "severe problems", to 5 = "extreme problems".By combining the level of each dimension, a unique state of health can be obtained.For the coding purpose, each health level is referenced by five digits.For example, code 12345 indicates no problem with mobility, slight problems with washing or dressing, moderate problems with usual activities, severe problems with pain or discomfort, and lastly, extreme problems with anxiety or depression.In contrast, code 11111 represents a lack of problems in all dimensions 10 .Between 11111 (no problems on any dimension) and 55555 (extreme problems or unable to on all dimensions), EQ-5D-5L can be used to describe a total of 3125 health states 19 .

EQ-5D-5L index
To obtain the EQ-5D summary index, a value (weight) is attached to each level in each dimension.The index is then calculated by subtracting the appropriate weight from 0 to 1, as 1 represents a full health status.The collection of index values (weights) for all possible EQ-5D health states will give rise to the value set.Most sets of EQ-5D values were generated from standardised assessment exercises whereby a study sample from the general population of a country or region was invited to rate their EQ-5D health states.In 2019, the EuroQol Group established a standardised assessment study protocol (EQ-VT) to produce a set of standard values for the EQ-5D-5L among different study populations.This protocol was developed based on the composite time trade-off evaluation technique (cTTO) and discrete choice experiment (DCE) to simplify the evaluation technique, and more importantly, to facilitate international comparisons 9 .The index utility value is attached to the responses on the EQ-5D-5L descriptive system based on the specific tariff of the Malaysian population 20 .The utility index value

EQ-VAS scores
By using EQ-VAS, the overall health condition from the patient's perspective on the day of answering the questionnaire can be elicited.It is scored on a scale ranging from 0 (worst imaginable state of health) to 100 (best imaginable state of health).

Data analysis
SPSS for Windows (version 28.0) was used for data analysis.The health status of each respondent were directly retrieved from the self-report questionnaires of EQ-5D-5L and EQ-VAS.The Malaysia EQ-5D-5L value set was then used to calculate the EQ index score 20 .All 3125 health states' EQ-5D-5L index scores were estimated after acquiring the EQ-5D-5L value set 19 .Each respondent's EQ-5D-5L index scores were calculated based on their self-reported health conditions.
Following that, descriptive summary statistics of EQ-5D-5L dimensions, EQ-5D-5L index, and EQ-VAS score were calculated for all the samples based on their sociodemographic characteristic (age, gender, race, married, education, household income, employment, and insurance) and medical profiles (types of cancer, stage of cancer, and comorbidity).The percentage of problems reported under the EQ-5D-5L dimensions, the means (95% confidence interval) of the EQ-5D-5L index, and EQ-VAS scores were determined for each subgroup for each sociodemographic variable.Secondly, Mann-Whitney U and Kruskal Wallis test was used to examine the significant difference between sociodemographic and medical profile characteristics with EQ-5D-5L dimensions, EQ-5D-5L index, and EQ VAS scores.The test was used as the data not normally distributed.
Lastly, multivariable analysis was conducted for the EQ-5D-5L index and EQ VAS score to analyse the relationships between multiple independent and dependent variables.The Universiti Kebangsaan Malaysia (UKM) Research Ethics Committee gave its clearance for this work, and it was conducted in accordance with UKM's established standards for ethical research.Study was performed according to the declaration of Helsinki.Prior to participating in the study, each patient gave their informed consent, which the institution's ethics committee had approved.

Ethical approval and consent to participate
This study has been approved by the Research Ethics Committee of Universiti Kebangsaan Malaysia (UKM) and the research ID was JEP-2020-504.Informed consent was obtained from all the participants.

Results
There were 235 individuals in the final analysis.Among the 377 respondents who tapped the survey link on the REDCap software, 142 respondents (37.7%) with incomplete questionnaire were excluded.Table 1 shows the sociodemographic and medical profile characteristics.The mean age was 43 years (range 22-76 years old).The majority of them were females (77.9%),Malays (80.9%), and married (76.6%).A small number of patients (7.7%) had a Master's degree or Ph.D. education level while the rest had a Diploma (24.3%) or Degree (26.4%).Most of them had a monthly household income of below RM 3000 (46.8%), 25.5% earned RM 3001-RM 5000, 12.8% earned RM 5001-RM7000, and 14.9% earned RM 7001 and above.
Table 4 shows the distribution of reported problems in various severity levels and dimensions, as well as the mean (SD) of EQ-VAS and EQ index scores by age group.Based on the results, age group was significantly associated with the dimensions of mobility and usual activity with p values 0.010 and 0.033 respectively.In contrast, the EQ-VAS and EQ index scores of self-care, pain/discomfort, and anxiety/depression dimensions were not associated with the age group.Patients 60 years and above reported the highest mean EQ-VAS value (85.73,SD = 11.8) while the highest mean EQ-5D-5L index score was observed among patients 35-44 years old (0.79, SD = 0.235).
The association between EQ-5D-5L dimensions, indexes, and EQ VAS scores with the independent variables is outlined in Table 5.Based on the analysis, the level of education was significantly correlated with all dimensions of EQ-5D-5L.Meanwhile, the stage of cancer, and comorbidity were also significantly correlated with all dimensions of EQ-5D-5L, except for the anxiety/depression dimension.In contrast, there was no significant correlation between marital status and insurance ownership with any outcome variables.However, age, gender, education, type of cancer, stage of cancer, and comorbidity showed a significant difference with the mobility dimension p-value < 0.05).More importantly, EQ-5D-5L indexes and EQ-VAS scores showed significant correlations with monthly household income, stage of cancer, and comorbidity.
All the significant variables in univariate analysis were inserted into the multivariate linear regression model to identify the significant predictors of EQ-5D-5L indexes and EQ VAS scores ( www.nature.com/scientificreports/(B), education levels (B = 0.097; p = 0.002), the stage of cancer (B = − 0.068; p = 0.000), and comorbidity (B = 0.102; p = 0.000) were significantly associated with EQ-5D-5L index.Based on the adjusted R-squared value, all of the independent variables explained 25.7% of the influence of the factors on health status by EQ-5D-5L index.Meanwhile, the stage of cancer was the only significant predictor of EQ-VAS scores (B = − 4.988; p = 0.000).The adjusted R-squared value for EQ VAS was 13.4%.All the factors were not significant predictors of EQ-VAS scores, except for the stage of cancer.

Discussion
Based on literature review, there are very few studies in Malaysia that have reported EQ-5D-5L for patients with primary cancers in Malaysia [21][22][23] .The health status of the cancer population was obtained using EQ-5D-5L dimensions, EQ-5D-5L indexes, and EQ VAS scores.These findings represent vital insights into the HRQoL of cancer patients in Malaysia, specifically on the variation of HRQoL among different sociodemographic groups.
Most significantly, it facilitates the conduct of cost effectiveness studies that incorporate QALY as a health outcome.By having a set of norm scores as a point of reference, the HRQoL of respondents obtained from any studies can be compared with the general population, especially among individuals with particular diagnosis which are of similar ages 24 .
Overall, the mean EQ-5D-5L index and EQ-VAS scores of cancer patients in this study were 0.76 and 81.00, respectively.Their mean EQ-VAS score was lower (85.52,SD 12.3) 20 while the median EQ-5D-5L index (0.79) was higher than the general Malaysian population (0.336).Furthermore, the mean values of the EQ-5D-5L index were higher than two published studies that reported the utility values of patients with colorectal cancer based on EQ-5D-5L in Iran and China 6,11,25 .The difference in values could be attributed to the variation in the populations sampled, the value sets employed, and also the versions of the EQ-5D used in the survey 26 .Moreover, the Chinese EQ-5D-5L tariff was derived from the preferences of the Chinese and Iranian general public, both of which could be different due to cultural and demographic variations.Similar differences were observed when comparing with Asian countries such as Thailand (EQ-5D-5L index 0.90, EQ-VAS score 80.00) 27 .
Next, the study results revealed that most of the cancer patients did not experience any problem with mobility, self-care, and usual activity.In addition, no patient reported extreme problems in the dimensions of mobility, self-care, and pain/discomfort, in contrast to the dimensions of usual activity and anxiety/ depression.These results were in line with the findings in other countries whereby the first three dimensions of EQ-5D were commonly associated with fewer reported problems compared to the last two dimensions 15,26,[28][29][30][31][32][33] .Based on previous studies, the percentage of reported problems in the dimension of anxiety/depression increased with age [28][29][30]34 . Howver, the opposite finding was shown in our results in which anxiety/depression problem was more prevalent in the younger population.Generally, there was a high prevalence of patients aged 35-60 years and above 60 years with no reported problems in the dimension of anxiety/depression.According to a study in China, the difference in age values could be explained by the psychological pressures experienced by younger generation compared to older patients 15 .In addition, no significant difference has been found between marital and insurance status across all dimensions of EQ-5D-5L.Previous reports have emphasized equal impacts on quality of life across different marital statuses 22,35 .Meanwhile, the lack of impact of insurance status on cancer patients may be attributed to Malaysia's status as an upper-middle-income country that provides subsidized public health services to all citizens through national taxation or lack of knowledge regarding health insurance 36 .
Apart from that, we also assessed if the patient's sociodemographic and medical profile characteristics were associated with EQ-5D-5L index and EQ-VAS scores.The current study demonstrated that education level, the stage of cancer, and comorbidity were significant predictors of the EQ-5D-5L index.However, only the stage of cancer was a significant predictor of EQ-VAS.Moreover, adult patients were more likely to have more comorbidities and advanced stage of cancer, thus further limiting their physical functions and compromising their HRQoL.This result was in contrast with a previous study in which comorbidities did not show any significant influence on health utility 22 .This could be explained by the different types and number of comorbidities that might affect people's perceptions and preferences during health state valuations 8 .Our results concurred with another study that reported education as an important factor that influenced health utility 11 .A high education level improved  www.nature.com/scientificreports/ the patient's perceptions of their disease and treatment whereas a low level of education can result in a delay in treatment-seeking 25 .However, in a Canadian EQ-5D-5L valuation paper, educational level was not linked to the value of health states 8 .A plausible explanation for this could be the underlying differences in the socioeconomic status, as well as the structure and accessibility of healthcare systems between both countries, hence influencing the correlation between educational level and health states 1,37 .This study has several limitations.Firstly, only patients from the three most common types of cancers were included, thus limiting the generalisability of the results.Secondly, the Covid-19 pandemic necessitated the study to be undertaken fully on the digital platform, thus no direct interaction and face-to-face meetings with respondents were possible during data collection.Consequently, certain respondents without social media accounts or direct internet access could not participate in the survey.Previous studies reported that online surveys tend to have a lower response rate [38][39][40] , and incentives such as consolation money can sometimes improve the response rate 41 .Furthermore, response rates are typically lower among racial and ethnic minority groups, as well as those www.nature.com/scientificreports/with poorer health status, lower income, and less education 42 .Additionally, a study found that breast cancer patients who were older, with a lower level of education, and a poorer quality of life preferred paper-based surveys compared to electronic surveys, thus indicating the potential barrier of data collection in this population 43 .

Conclusions
Health state utilities is a highly potential tool to measure the effectiveness of treatment modality as determined by the treatment outcome by assessing the life expectancy of cancer patients based on their QALY.This study provided vital information about the EQ-5D-5L for the top three common types of cancers (breast, colon, and lung) in the Malaysian population.The findings highlighted disparities across sociodemographic groups in the self-reported health status measured by EQ-5D-5L.Therefore, healthcare providers and researchers should focus on the assessment of patients' individual experience of disease and preference for treatment.

Table 1 .
Sociodemographic and profile medical characteristics of respondents (N = 235).

Table 2 .
Percentage of respondents for levels 1-5 by dimension.

Table 3 .
The central tendency and dispersion of EQ-5D-5L index and EQ-VAS scores.

Table 4 .
Percentage of cancer patient population sample reporting levels 1 to 5 dimensions, EQ-5D-5L indexes, and EQ-VAS score by age group.Significant values are in bold.

Table 5 .
Association of sociodemographic and medical profile characteristics with EQ-5D-5L dimension, indexes and EQ-VAS (N = 235).*Correlation is significant at the 0.05 level (2-tailed).1Mann Whitney U test.2Kruskal Wallis test.Significant values are in bold.

Table 6 .
Multivariable regression models for sociodemographic and medical profiles with EQ-5D-5L index and EQ VAS scores.Bold values are significant at p value < 0.05.SE standard error.